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Levemir
Levemir is Novo Nordisk A/S's worldwide brand name for insulin detemir, a long-lasting insulin analog that lasts up to 24 hours in humans. Its chief benefits according to Novo are a "peakless" action, less weight gain than other insulins, and less day-to-day variability than NPH or Lantus insulins. Levemir has been shown (by the manufacturer) to vary less day-to-day than NPH or Lantus. It was also found to vary less between patients. Veterinary use Doctors' Rand and Fleeman's protocol for Levemir use in dogs is at this link. Levemir has now become part of the treatment program for dogs who metabolize the usual Intermediate-acting insulins too quickly, thus having less duration than would normally be expected from them. The protocol calls for a small dose of the Long-acting insulin once daily, with the Intermediate-acting insulin being used twice daily, as before. In this example, a Rottweiler continues her twice daily Lente insulin with the addition of Levemir once daily with the Levemir dosage calculated at 0.25 units per kg of weight. The Lente insulin was being given at 1 unit per kg at the time the Levemir was added; there are no indications the Lente insulin doses were changed when Levemir was added. The example at the reference link indicates a marked change for the better in blood glucose control 2 weeks after adding Levemir to the insulin regimen. It's also worth noting that the Lente insulin is U40, pork origin, and the Levemir is a U100 analog insulin. Though they can't be used in the same syringe, this is an example of using insulins of different origins successfully. Levemir will need different doses in different species! A dog dose is likely to be about 1/4 of a human dose, per kg weight. The reason is revealed in the EU testing documents. Levemir was found to be only 25% as effective as expected in humans, and so the concentration was quadrupled in the marketed version. But note: the 25% efficacy figure at 6nmol/unit in humans was not consistent between species, due to the albumin-binding side-chain physically interfering with insulin receptors, which vary in structure by species. Dogs and pigs found it 100% effective, but in mice and rabbits it was only 1/15 as effective per nmol. According to the tests, therefore, the marketed concentration of 24nmol/unit will seem about normal to humans but 4 times stronger than normal to dogs. Usage and Handling Levemir comes in 3ml pen cartridges, prefilled 3ml insulin pens and 10ml vials. Cartridges, when available, are compatible with all Novo Nordisk insulin pens including the Novopen Junior and Novopen 3 Demi, which both allow half-unit doses. Dosages finer than 1/2 unit increments must be dispensed by using a syringe with the cartridge, which is in this case quite easy. Pictorial at link below Do not reinsert a cartridge into a refillable pen, or use a disposable pen mechanism, after using it with a syringe, to avoid stress on the pen mechanism and likely destruction of the cartridge or pen. Levemir's shelf life is 2 years. After first opening the product must be stored, officially for a maximum of 6 weeks, not above 30°C. It may be stored in a refrigerator (2°C - 8°C) not near a freezing compartment. Do not freeze. Protect from light. The insulin is clear and does not need rolling or agitation. Pens in use are recommended not to be refrigerated, but stored in a dark cool place below 30°C. Pen cartridges used with a syringe may of course be refrigerated for longer life. Levemir appears to work fine when stored overnight in syringes for prepared dosing. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections." Technical details Levemir is a clear solution created by genetically engineered yeast. It is analogous to human insulin, but includes a "fatty acyl side chain" that binds temporarily to albumin (found under the skin and in abundance in blood plasma)(98% albumin-bound ) and makes the molecule "cling" to the bigger albumin molecules for a while before releasing -- making the molecules slower to enter and exit the bloodstream, and slower to enter the cells. At an ADA Symposium prior to Levemir's US approval in 2005, Novo Nordisk claimed that if NPH has a patient to patient variability of 60%, Lantus (insulin glargine) then has a 40% variability, and Levemir a 25% rate of variability. Unlike its long-acting rival Lantus, Levemir's time-delay action occurs in the bloodstream and at the target sites, not only at the subcutaneous injection site, and doesn't depend as much on the properties of the injection site or the suspension like NPH and other analog mixed insulins. Human insulin is altered to produce insulin detemir (Levemir) by omitting the amino acid Threonine at insulin B chain position #30 and attaching a C14 fatty acid chain to the amino acid at position #29, Lysine. The combination of the omission of the threonine amino acid at position #30 on the B insulin chain and the addition of the fatty acid side chain at position B-#29 binds the insulin heavily to albumin. Also, the insulin now has more self association tendencies (remaining in hexamer form) than unaltered human insulin. Having the insulin stay in hexamer form longer before breaking down into dimers and monomers means slower absorption, which works out to slower onset, peak and longer duration. The mean duration of action for Levemir ranges from 5.7 hours at lower dosages to 23.2 hours at the higher ones. For doses in the range of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours to approximately 14 hours after being administered. Injection sites should be rotated to avoid lipodystrophy, as with any insulin. The good news is, according to Novo Nordisk, Levemir's stretched-out action in the bloodstream makes its absorption less dependent on injection site conditions (and on rotation) than Lantus. This claim is boosted by Novo's findings of lower day-to-day variability on Levemir compared to Lantus. Levemir was tested against NPH/isophane insulin for EU approval. During the tests, (see page 6) Levemir at usual insulin concentrations (6nmol per unit) was found in humans to have only about 25% of the glucose-lowering action of the same dose of NPH, so the concentration was increased fourfold to 24 nmol/unit to compensate. The version being marketed has a concentration of 24 nmol/unit, 2400 nmol per mL. Note that this efficacy problem differs between species, see veterinary use above. Analog Insulins: amino acid sequences Analog Insulins: pharmacokinetics These are human activity profiles. References More Information *Mechanism of Protracted Metabolic Effects of Fatty Acid Acylated Insulin, NN304 (Insulin Detemir/Levemir), in Dogs: Retention of NN304 by Albumin Hamilton-Wessler M, Ader M, Dea M, Moore D, Jorgensen PN, Markussen J, Bergman RN., 1999, Diabetologia *Dosing information on Levemir for dogs Rand, Jacqueline, Fleeman, Linda, University of Queensland *Medical summary sheet Diabetes Monitor *Levemir's EU approval testing details EMEA *Video: Basal/bolus method, desired vs. practical insulin action, and Levemir mechanism Novo Nordisk *How to Achieve a Predictable Basal Insulin? Kurtzhals P, 2005, Diabetes & Metabolism *Insulin Detemir Under Steady-State Conditions: No Accumulation & Constant Metabolic Effect Over Time With Twice-Daily Use in Type 1 Diabetes Bott S, Tusek C, Jacobsen LV, Endahl L, Draeger E, Kapitza C, Heise T., 2006, Diabetic Medicine (UK) *Insulin Detemir: From Concept to Clinical Experience Home P, Kurtzhals P., 2006, Expert Opinion on Pharmacotherapy *Leeds NHS UK-Insulin Guide Category:Insulins Category:Analogs Category:long-acting Category:Novo Nordisk Category:R-DNA/GE/GM Category:Rx Status Category:Intravenous use NO Category:Meta-cresol Category:Phenol Category:Content Category:Currently marketed insulins